Objective: Mismatch repair deficiency (dMMR), high microsatellite instability (MSI-H), and high tumor mutation burden (TMB-H) are predictive and prognostic biomarkers in endometrial cancer. We aimed to characterize the racial/ethnic distribution of molecular markers and the clinical characteristics among endometrial cancer patients with TMB-H and MSI-H/dMMR.
Methods: The Endometrial Cancer Molecularly Targeted Therapy Consortium is a centrally verified clinical and molecular repository. Patients with endometrial cancer who underwent tumor profiling were included. TMB-H was defined as ≥10-12 mutations per megabase. MSI-H was determined by next-generation sequencing or polymerase chain reaction, and dMMR by loss of MLH1, MSH2, MSH6, or PMS2 on immunohistochemistry. Tumor biomarker positivity was defined as TMB-H and/or MSI-H/dMMR. Overall survival was assessed using Kaplan-Meier and Cox proportional hazard models.
Results: Among 742 patients, 22 % (n = 164) were biomarker positive: 12 % (n = 87) had both TMB-H and MSI-H/dMMR, 8 % (n = 63) had MSI-H/dMMR alone, and 2 % (n = 14) had 14 TMB-H alone. Only 9 % of non-Hispanic Black patients had biomarker positive tumors compared to 26 % of patients from other racial/ethnic groups. Pathogenic POLE mutations were rare (<1 %, n = 5). Patients with TMB-H had a higher proportion of high-risk histologies (43 %) than those with MSI-H/dMMR (24 %). Biomarker positive tumors were associated with a lower risk of death compared to biomarker negative tumors (aHR 0.63, 95 % CI: 0.46, 0.88).
Conclusion: Less than 10 % of non-Hispanic Black patients with endometrial cancer had TMB-H and/or MSI-H/dMMR, and biomarker positivity was associated with improved survival. Prospective studies are necessary to elucidate how these molecular differences impact treatment and outcomes.
Keywords: Endometrial cancer; Microsatellite instability; Mismatch, repair deficiency; Tumor mutational burden.
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